The present invention relates to methods of inhibiting plaque formation on hard and soft tissue surfaces. In particular, the present invention relates to preventing dental plaque formation using non-antibacterial tetracyclines.
For several decades now, there has been an increased awareness of the relationship between plaque formation on tooth surfaces and dental cavities or caries. Dental plaque is generally regarded as a film of bacteria, bacterial polymers, salivary polymers, remnants of epithelial cells and leukocytes. The bacteria, principally Streptococcus mutans, is part of the naturally occurring microflora of the oral cavity. The bacteria use natural sugars such as sucrose and glucose included in the diet as a nutrition source and produce cement-like polymers which bind to the enamel tooth surface. Once bound, the opportunistic bacteria cause demineralization of the enamel by secreting acids and ultimately caries. Although the roots of teeth lack enamel, plaque formation may also be found below the gingival margin. Such plaque formation ultimately leads to root caries, a leading cause of tooth loss in adults. Root caries can be especially prevalent when, due to periodontal disease, the gums and alveolar bone both recede and expose the roots.
In the past, most efforts aimed at reducing plaque formation and dental caries have included reducing sugar intake, regular brushing, flossing and periodic removal of the plaque by dental professionals.
In some cases, plaque formation on tooth surfaces may become excessive and even pathologic. In these situations, it is often necessary to institute prophylactic measures in addition to those described above. In the past, broad spectrum antibiotics such as tetracyclines and metronidazole have been used in the treatment of periodontal disease to reduce oral cavity microflora, which is the most virulent aspect of plaque formation. Although antibiotic agents are effective in reducing the bacteria responsible for plaque formation, extended periods of antibiotic administration are avoided due to high incidences of side effects. Side effects most often associated with long-term antibacterial agent usage include intestinal disturbances, overgrowth of yeast and fungi, and most importantly, the development of antibiotic-resistant bacterial strains.
As stated above, tetracyclines are broad spectrum antibiotics and are active against most oral cavity microflora. The tetracycline compound exhibits the following general structure: ##STR1## The numbering system of the ring nucleus is as follows: ##STR2##
The tetracycline molecule is amenable to substantial modification without losing its antibiotic properties. Examples of modifications that may and may not be made to the basic tetracycline structure have been reviewed by Mitscher in the Chemistry of Tetracyclines, Chapter 6. According to Mitscher, the substituents at positions 5-9 of the tetracycline ring may be modified without complete loss of antibiotic properties. Changes to the basic ring system or replacement of the substituents at positions 1-4 and 10-12, however, generally lead to synthetic tetracyclines having substantially less or effectively no antibacterial activity. For example, 4-dedimethylaminotetracycline is commonly considered to be a non-antibacterial tetracycline.
Various properties of antimicrobial and non-antimicrobial tetracyclines are known. For example, it is known that antimicrobial and non-antimicrobial tetracyclines can bind to metal ions such as calcium. Tetracyclines are also known inhibitors of collagen destructive enzymes such as mammalian collagenase, a calcium dependent zinc-metalloproteinase. Collagen is a major component of connective tissue matrices such as those in the bone, synovium, eye, skin, tendons and gingiva but not tooth surface enamel.
U.S. Pat. No. 4,666,897 to Golub, et al. discloses tetracyclines, including commercially-available antimicrobial forms of the drug, inhibit excessive bone resorption and collagenolytic enzyme activity. U.S. Pat. No. 4,704,383 to McNamara, et al. discloses tetracyclines having substantially no effective antibacterial activity inhibiting collagenolytic enzyme activity in rats. Moreover, McNamara, et al. also disclose that non-antimicrobial tetracyclines reduce bone resorption in organ culture.
Although some oral hygiene products such as dentifrices have been recently introduced to combat the problem of plaque formation, a complete solution remains elusive.
In view of the desire to reduce plaque formation on tooth surfaces and further in view of the desire to avoid using antimicrobial antibiotics to accomplish this result, it is an object of the present invention to provide an improved method of inhibiting plaque formation on tooth surfaces.
It is a further object of the present invention to provide a method of inhibiting plaque formation on tooth surfaces using non-antibacterial tetracyclines.